The Youth Pill

Rats and mice have been the overwhelming favorites in the study of CR, whose discovery was presaged by the reports in the early 1900s that fasted lab rodents are strangely resistant to cancer. CR’s anticancer effects in rodents have long been one of the phenomenon’s main attractions to medical researchers. In one study using four different strains of mice, 51 percent of elderly female rodents on normal diets developed tumors, while only 13 percent of their calorie-restricted counterparts did. In mouse models of cancer, CR has been shown to suppress tumors of the breast, prostate, intestines, and brain, as well as blood-cell cancers, such as leukemia. McCay reported that none of his calorie-restricted rats developed tumors until after they were put on normal diets at fairly advanced ages.

Some strains of rats often die of cardiomyopathy, an inflammation-linked degeneration of heart muscles. In a representative rat study, 95 percent of two-year- old rats on all-you-can-eat “ad libitum” diets suffered from the condition, while only 15 percent of those that were fed 40 percent fewer calories did. The same study showed that CR nearly eliminated kidney disease, another major killer of old rats, and attenuated the age-related degeneration of their adrenal and thymus glands, as well as of their livers.

Research on members of the Calorie Restriction Society, a group of people who practice CR, has shown that eating about 30 percent fewer calories than are contained in typical Western diets dramatically reduces blood pressure, LDL cholesterol, and other risk factors for heart disease. The hearts of middle-aged CR practitioners have been found to be youthfully elastic, resembling those of nonpractitioners about sixteen years younger.

One of CR’s most important benefits is its ability to knock down chronic, low-level inflammation that’s thought to drive many diseases of aging and is also likely a major component of normal aging. Along the same lines, CR keeps back overzealous immune cells behind inflammatory autoimmune diseases. Yet at the same time it retards age-related immune-system weakening.

In a study of mice that were genetically altered to develop a rodent version of Alzheimer’s disease, CR halved brain levels of betaamyloid—proteinaceous gunk whose accumulation is thought to be a key culprit underlying the disorder’s massive loss of neurons. CR also protects rodents against the kind of brain damage caused by Parkinson’s disease and strokes.

Aged animals on CR look much younger than peers on ad lib diets. “The skin of a [rat on CR] appears like that of a young one,” McCay marveled in one report. Older rodents on CR don’t lose hearing acuity, as do peers on normal diets. In both rodents and monkeys, CR greatly retards the inexorable loss of muscle tissue with age that represents a major cause of frailty in the elderly.

Despite all these pluses, however, it’s not a given that CR compresses morbidity toward the end of life. That may sound like a paradox. But it’s possible that CR postpones diseases of aging in people without abbreviating the amount of time the ailments subtract from health span. Thus, it’s not immediately obvious that CR mimetics would help avert the crushing medical burden portended by the aging of the population—they might only delay its full measure of pain.

Happily, though, the literature on CR contains hints that it can, and often does, compress morbidity in addition to extending life. That means there’s a good chance that taking CR mimetics would help many of us keep going in pretty good shape until a generalized state of fragility is reached that leads to precipitous collapse after a minor perturbation. In other words, it would enable an extralong, vibrant life followed by the kind of speedy demise we all hope for—one that doesn’t leave us staring blankly for years at nursing home walls, confront our families with painful decisions about how much heroic medicine to try toward the end, or rack up huge bills that darken our loved ones’ lives.

I picture this situation akin to the elegantly simple game of Jenga, which everyone from preschoolers to great-grandparents can play competitively. Players begin the game by setting up a compact tower of small, stacked blocks of wood. Then they take turns delicately extracting its embedded blocks and stacking them on the top to build it higher. The goal is to keep the structure standing until it is so full of weak spots that it suddenly crashes down at the lightest touch—the last player to touch it before the collapse loses.⁹

CR often seems to play bio-Jenga. In fact, about a fourth of rodents on CR suddenly keel over without warning at the end of their extraordinarily long lives, and close examination of their tissues after death shows no signs of organ degeneration. The cause of death in such cases isn’t clear. University of Southern California gerontologist Caleb Finch speculates that because blood-glucose levels in CR rodents tend to be abnormally low, old ones may sometimes die from cardiac arrest brought on by transient drops in blood sugar.

Richard Weindruch, a University of Wisconsin CR researcher, once described the mysterious deaths of such calorie-restricted rodents to me in a particularly telling way: “When you open them up [to inspect their organs], they look great,” he said. “The only apparent problem is that they died.”

Perhaps we shouldn’t be surprised if many obits in the approaching age of CR mimetics go something like this: “Jack Spry passed away on Friday at age 105 after a brief nonillness. Survived by his loving wife and kids, he was always the life of the party—including the one he attended on Thursday evening. His only major problem in later life was that it ended.”

Life-span studies with rodents have told us a lot about aging. They’ve also turned many gerontologists into grizzled experts on Murphy’s Law. There are an appalling number of ways for rats and mice wiling away their lives in cages to die prematurely. Insidious infections can traipse through. Previously unrecognized, late-onset genetic diseases can crop up. Subtle noises or smells that humans can’t register may freak out the animals, shortening their lives. As we saw earlier, aggressive male mice sometimes kill their cage-mates when no one is looking. Such risks are magnified in life-span studies of rodents on CR, which tend to be especially long, affording more chances for things to go wrong.

Temperature gyrations rank near the top of the list of possible disasters. Killer heat, remember, almost crashed McCay’s seminal CR experiment. Fifty years later, scientists in St. Louis conducting another CR study with rats lost many of their animals to overheating when an air-conditioning system failed. But history didn’t exactly repeat itself. The latter calamity turned out to be serendipitous, providing an important clue about what’s inside CR’s black box just when scientists were finally beginning to lift its lid—the prelude to development of CR mimetic drugs.

The St. Louis study was carried out at a Veterans Administration hospital by a group that included Arlan Richardson, then at Illinois State University, one of the first researchers to investigate CR’s mechanism at the molecular level. Now director of San Antonio’s Barshop Institute, Richardson was dismayed when he came to work one blazing summer day in the late 1980s and learned that the thermostat governing the air-conditioning system in the hospital where his rats were housed had malfunctioned. When the lab heated up, an alarm that was supposed to go off also failed. As the hours crept by, the temperature in the rat room rose to somewhere over 90°F. By the time one of Richardson’s colleagues discovered the accident, 86 of 128 rats had fatally overheated. They were twenty months old—middle-aged.

But there was a surprise: Three-quarters of the calorie-restricted rats had survived, while only 16 percent of the ones on ad-lib diets had. Apparently CR bestowed some sort of heat shield on rats. The fact that CR makes animals thinner was probably a factor—thin rats can shed heat faster than fat ones. But that didn’t fully account for the oddity, because a normally fed, unthin group that had formerly been on CR also survived better. Thinking it over, Richardson and colleagues realized that a much more interesting phenomenon had likely protected the CR rats.

Research dating from the 1960s had shown that a wide variety of cells exposed to elevated temperatures react by churning out “heatshock proteins,” which protect cells against heat and other forms of stress. It stood to reason that the ability to block cellular damage with heat-shock proteins fades with age along with everything else that goes downhill. If so, CR might postpone the downward slide, helping to make calorie-restricted rats relatively impervious to high temperatures. In 1993, Richardson and colleagues confirmed that, as suspected, the heat-shock response in CR rats remains youthfully robust as they age.

Their report provided some of the first evidence that switching on what’s now called the stress response is one of CR’s main anti-aging tricks. Fortuitously, the study appeared at about the time that a number of other scientists were finding that extralong life is correlated with cellular resistance to insults such as heat, radiation, and toxic chemicals. A couple of years later, the University of Colorado’s Tom Johnson and colleagues postulated that both gerontogenes and CR extend life span by bolstering the stress response.

Linking the stress response to CR has clarified one of the most uncanny things about calorie restriction: It basically averts or delays what ails you no matter who you are. If you’re a mouse that’s genetically prone to develop kidney-wrecking autoimmune disease at an early age, CR waves its magic wand over your kidneys and doubles your life span. If you’re a rat that tends to die of cardiomyopathy, CR fortifies your heart.

It’s tempting to simply attribute this versatile beneficence to the fact that CR slows the fundamental aging process, which presumably works about the same in all creatures and eventually brings on diseases of aging. But this explanation both clarifies little and explains away too much.

Here’s a better explanation that factors in the stress response: The induction of CR’s diverse benefits across species by a common stimulus (reduced calorie intake) shows that an evolutionarily conserved module is being activated. A key part of its triggering mechanism is a calorie-intake monitor. Its anti-aging outputs largely comprise different aspects of the stress response. As with the anti-aging module triggered by daf-2 and related gerontogenes, the outputs have been customized during the evolution of different species to protect against the somewhat different sources of damage underlying senescence in their specific body types and life histories. That gives the module its versatile, cure-what-ails-you power.

In 1998, veteran calorie-restriction researcher Edward Masoro, who is credited with building the University of Texas Health Science Center at San Antonio into a major center for aging research, strengthened the connection between the stress response and CR by pointing out that CR’s effects look a lot like “hormesis”—mentioned earlier, that’s the lingering resistance to harm from toxins and other insults induced by small doses of such baddies.

First described by a German pharmacologist in the 1880s, hormesis was an esteemed concept in toxicology before 1930. Some physicians even applied it therapeutically. It was based on findings that at first glance didn’t make sense (except to believers in Nietzsche’s dictum that hurtful things that don’t kill us make us stronger): Germicides in tiny doses speed the growth of microbes that they kill at higher doses. A little arsenic stimulates yeast metabolism. Low doses of X-rays boost animals’ resistance to infections. Today it’s thought that such examples of hormesis represent sustained activation of cells’ molecular protect-and-repair systems after exposure to stress.

But the idea was tarnished by its association with homeopathy, a dubious form of alternative medicine based on administering vanishingly small doses of drugs, and by the advent of radium-spiked elixirs that supposedly acted as energizers via hormesis. In 1932, a millionaire playboy named Eben Byers died at fifty-one after gulping down more than a thousand bottles of one such elixir over three years, causing a lethal amount of radium to build up in his bones and eat holes in them. The nationally publicized case inspired a crusty editor at the Wall Street Journal to come up with an unforgettable headline: THE RADIUM WATER WORKED FINE UNTIL HIS JAW CAME OFF.

Hormesis was further linked to the weird and wacky in the 1950s, when earlier studies that had shown that low-level radiation could promote cellular growth via hormesis were twisted into plots for horror movies such as Them! and Godzilla, whose monsters supposedly got gigantic after exposure to atomic bomb radiation. The rampaging protagonist in Attack of the 50 Foot Woman also apparently underwent radiation hormesis, as did a certain amount of her clothes, after encountering a large, radioactive alien. All of which goes to show once again that what doesn’t kill you makes you a lot stronger, bigger, meaner, and, on occasion, more scantily clad.

Still, hormesis is real and important, and it nicely explains anomalies that matter to all of us: Low doses of penicillin can stimulate bacterial growth; exposure to dirt and germs early in life lowers risk of allergies and asthma; and vigorous exercise, which seemingly should cause oxidative damage in cells, apparently strengthens them against it.

Hormesis may also partly account for the health benefits of consuming lots of vegetables, which contain natural, mildly toxic compounds that are known to stimulate aspects of the stress response in animals that eat them. In fact, scientists have long thought that children generally hate many vegetables as an evolved response to avoid such chemicals, which typically have telltale bitter tastes. We adults, however, have learned to love a number of bitter poisons that plants produce in their futile attempts to convince marauding omnivores like us to leave them alone. A neurotoxin called caffeine is one of them—wake up and smell the hormesis brewing.

Masoro and another gerontologist, Suresh Rattan at the University of Aarhus in Denmark, have made a compelling case that CR acts as a form of chronic, mild stress that continually invokes hormesis. That activates cellular systems that protect and spruce up DNA and other molecules degraded by aging. The fact that calorie-restricted rodents have chronically elevated blood levels of a hormone called corticosterone, a major driver of the stress response, suggests that they’re right.

Hormesis isn’t all there is to CR’s anti-aging effect. For instance, CR has been shown to lower the output of free radicals from cells’ energy-generating reactions, which, as Masoro has noted, doesn’t seem properly classed as a hormetic phenomenon. But an appealingly large number of things about CR are consistent with the idea that it draws much of its anti-aging power from hormesis.

For instance, hormesis fits neatly with CR’s evolutionary logic, which U.S. and British scientists independently proposed in the late 1980s. Their main insight was that CR triggers a “starvation response” that evolved long ago to help organisms outlast famine. The response is thought to entail cutting back on growth and reproduction in order to devote more energy to mitigating cellular damage, enabling organisms to age slowly and stick around to pass on their genes to future generations when conditions improve. Evolution might have cobbled together the starvation response by wiring nutrient sensors to various hormetic pathways.

This theory is widely accepted in gerontology, but not everyone in the field buys it. One skeptic is Steven Austad, who notes that unpublished data on mice living in the wild show that they rarely live long enough to benefit from putting the brakes on aging in order to ride out hard times. In fact, winter cold, predators, infections, and other mortal risks eliminate close to 99 percent of them in less than a year. Because they’re long gone before reproductive senescence normally sets in, there would be no reason for them to evolve a slow-aging starvation response.

So how does Austad explain CR’s anti-aging effects?

His alternative theory highlights the fact that when starvation looms, hungry animals forage more widely than they usually do. Nematodes, for example, are known for crawling off petri plates and making getaways during calorie-restriction experiments. Calorie-restricted rats tend to get frantically active, as if trying to desperately forage—they’ve even been known to run themselves to death on exercise wheels. A similar phenomenon may explain why some 80 percent of people suffering from anorexia nervosa become hyperactive.

When engaged in such “hard foraging,” as gerontologist Caleb Finch calls it, animals branch out and eat unfamiliar things, exposing themselves to toxins not present in their regular food. Indeed, it’s likely that most plants available to eat during tough times are rich in toxic chemicals, otherwise they’d already have been consumed. Thus, animals that engage in hard foraging probably have evolved very robust mechanisms to fend off damage from poisons as part of their starvation response. In Austad’s view, the main reason that CR so handily extends life span in rodents is that they’re geared by evolution to harden themselves against toxins as hunger sets in. The slowed aging that results from this erection of hormetic shields is an inadvertent fringe benefit rather than something selected for by evolution.

These two theories aren’t necessarily mutually exclusive—the different evolutionary forces they contemplate may both have helped foster a conserved anti-aging module triggered by CR. In any case, both have the same basic bottom line: The power to slow aging is closely tied to the kind of advantage that evolution would favor—helping species ride out prolonged stresses that have been coming at them for billions of years. Indeed, the ability to dial up durability seems so handy that it’s probably been around as long as living things have. And whenever evolution has been called on to confer it on a new species, it has been able to recycle existing metabolic machinery.

All this explains why different types of extraordinarily long-lived animals bear striking resemblances. For instance, both normal mice on CR and long-lived dwarf mice have abnormally low blood levels of IGF-1, insulin, and glucose, as well as reproductive deficits, unusually small body size, slowed maturation, and low average body temperatures. Some of these commonalities, such as low insulin and body temperature, have been observed in other long-lived animals, such as naked mole-rats, as well as in long-lived humans.

Still, nothing is simple in biology. Different methods of restricting worms’ food intake, oddly enough, have been found to activate somewhat different sets of genes and metabolic pathways in the animals. And CR has been shown to extend the already-long lives of Ames dwarf mice, which indicates that it switches on at least some anti-aging mechanisms in the rodents that are separate from those activated by their gerontogene. It’s also notable that long-lived dwarf mice tend to get fat as they age, while calorie-restricted mice are very lean.

Evolution has plainly composed variations on its life-span-extension theme. But the commonalities stand out more than the diversity. The stress response comes closest to qualifying as a standard feature of longevity enhancement, and because of that, hormesis theory arguably has more explanatory power than any other big-picture idea about CR. If you tilt the theory slightly and squint at it sideways, you can even get it to explain why the giant movie monsters of the 1950s were terribly hard to kill: Besides undergoing radiation hormesis, they were so busy ravaging the landscape that they had no time to eat and so were probably calorie-restricted as well—they were doubly hardened by hormesis.

Some party-pooping gerontologists argue that calorie restriction, and by extension CR mimetics, is likely to confer only minor human lifespan gains, or maybe none at all. They have their reasons.

First, CR’s well-known downsides loom large to the pessimists: It can make you so skinny that strangers think you’re sick, thin your bones and muscles, make you feel too tired to exercise, make you painfully sensitive to cold temperatures, make women infertile, and slow wound healing. It’s contraindicated for pregnant women and growing children. It lowers white-blood-cell counts and has been shown to make rodents more likely to die from influenza infections. Avoiding malnutrition on CR is tricky and time-consuming. CR also complicates the social pleasure of eating with friends.

Then there’s the hunger. CR enthusiasts claim that it doesn’t bother them much, and that you can deal with it by eating lots of high-bulk, low-calorie foods such as green leafy vegetables. But when I once tried CR for a few days, I found that it was impossible to fool my internal calorie monitor. After a while I felt like Templeton, the voracious rat of Charlotte’s Web—when told by an old sheep that he would live longer if he ate less, he countered, “Who wants to live forever? . . . I get untold satisfaction from the pleasures of the feast.” At least I was never as far gone as Clive McCay’s poor canines: When he put dogs on severe, calorie-restricted diets, they went psycho—unlike normal dogs, they would eat dog meat, driven to cannibalism by craving.

Pessimists say that truly effective CR mimetics might well induce many of the ill effects of CR’s strenuous dieting, possibly including relentless hunger. I don’t buy this, for there are many examples of drugs that confer gain without pain that once seemed unavoidably tied to their benefits. People prone to paralyzing stage fright, for example, formerly popped tranquilizers or knocked back a couple of whiskeys before going onstage. In those days, wooziness and emotional dulling seemed the inevitable costs of suppressing the racing heart, sweating palms, and other manifestations of the “fight-or-flight response” that makes stage fright so awful. Now stage performers take small doses of beta-blockers to suppress the fight-or- flight response without any loss of mental clarity or emotional force. Thus, I think it will be possible to develop what Austad has termed “selective CR mimetics,” drugs that confer CR’s benefits without its main downsides.

The pessimists also maintain that CR’s dramatic effects in rodents have misled us about how it would work in humans. Gerontologist Leonard Hayflick, for example, argues that typical lab rodents are overfed couch potatoes that die young. Thus, subjecting them to CR merely eliminates life-shortening “overnutrition” and boosts their life span to what it would have been in the wild if they were protected from its usual hazards. It follows that CR doesn’t really push the envelope on rodent longevity and is very unlikely to do so in humans.

But while mice in the wild tend to be leaner than lab rodents, they’re obviously quite fertile and thus probably not truly calorie-restricted. Indeed, Austad has found that ounce for ounce of body weight, wild mice actually consume about the same amount of calories that lab mice typically do. He and colleagues have also demonstrated that wild mice on CR (actually, their grand-offspring) show lower mortality and compelling signs of slowed aging late in life. (For reasons that aren’t clear, though, it increases their mortality early in life.)

Here is perhaps the pessimists’ best shot: The evolutionary pressures that shaped the starvation response in rodents have never applied to humans, and so there’s no reason to think we would react to long-term CR the way they do. Unlike small animals with fast metabolisms, we big mammals have relatively large bodily reserves that can see us through tough times without the radical move of forgoing growth and reproduction in order to slow aging. Further, if food is scarce in one place, far-ranging creatures like us simply move on to where it’s not. Thus, evolution has had no reason to maintain the starvation response in our kind. It follows that the ancient anti-aging module that underlies the response’s effects in rodents and other animals has probably lost its power in large, mobile primates like us—just as we and our fruit-eating primate relatives have lost the ability to synthesize vitamin C. (Over many generations, inherited traits that aren’t favored by natural selection tend to erode away via random genetic mutations.)

Optimists counter that CR has extended life span in just about every species in which it has been tried, indicating that the evolutionary pressures that gave rise to and refined it are remarkably ubiquitous across niches, species, and time. Thus, the argument that we’re an exception smacks of special pleading—a leap of gloom.

The case for optimism has also been strengthened by reports from two ongoing studies of CR’s long-term effects in rhesus monkeys, one initiated in 1987 by scientists at the National Institute on Aging, and the other in 1989 by Weindruch and colleagues at the University of Wisconsin. Definitive data on whether CR extends the primates’ life spans aren’t expected for years. But like rodents on CR, the monkeys are very lean and appear to be protected from the pro-aging, inflammatory effects of visceral fat; their cells have remained youthfully sensitive to insulin; they don’t show the usual age-associated rate of muscle wasting; and there’s evidence that free radical damage in their muscles has been slowed.

In mid-2009, Weindruch’s group made a splash by reporting that CR has indeed slowed aging in their primates—while 37 percent of control monkeys on normal diets had died, only 13 percent of the ones on CR had. The claim of slowed aging was somewhat controversial, however, because some of the monkeys on CR had died from causes deemed unrelated to aging, such as from gastric bloat; unless such deaths were excluded from the analysis, the CR group’s longer survival wasn’t statistically significant. Critics have argued that such deaths might actually be related to CR, hence excluding them may exaggerate CR’s survival benefits.

But other data from the study strongly suggest that the CR really does slow aging in primates, probably extending their life spans by 10 percent to 20 percent, and that much, if not all, of that extra time is spent in remarkably good health. Compared with controls, the CR monkeys have greater lean muscle mass, significantly less age-related brain atrophy, half as much cancer, half as much cardiovascular disease, and zero diabetes. Overall, the rate of age-related diseases in the CR animals has been about a third that of the controls. And seeing is believing: Pushing twenty-eight years of age, about the average life span of rhesus monkeys, the ones on CR look to be lean, sleek, vibrant-looking adults, while controls have the hunched, frail, droopyskin look of elderly humans.

Correlates of slowed aging have also been observed in people who have subjected themselves to CR for years, as well as in volunteers for an ongoing federally funded project to study CR in controlled clinical trials. In 2006, one of the first reports from the latter, called CALERIE, or Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy, showed that human responses to CR include lower insulin levels, just as in rodents.

One unintended study of CR has also shed light on its long-term benefits in people. It began in 1991, when eight intrepid earthlings launched a two-year voyage inside Biosphere 2, a three-acre glass-enclosed ecosystem in the Arizona desert that was bankrolled by Texas billionaire Ed Bass. Among them was sixty-seven-year-old physician Roy Walford, one of gerontology’s most colorful figures. Sporting a shaved head and rakish Fu Manchu mustache during his later years, Walford first won national fame in the 1940s when he and a friend figured out a way to pick winning numbers in roulette and quickly won more than forty thousand dollars in Reno and Las Vegas. They used the money to buy a yacht and cruise the Caribbean.

His later adventures included walking across India to check meditating swamis’ temperatures (he wondered whether they could lower them at will), exploring Amsterdam’s underground drug scene, and breaking a leg trying to pop a wheelie on his motorcycle while riding along Santa Monica Boulevard in Los Angeles. He was also a gifted scientist known for pioneering studies on immune-system aging and CR. With Wisconsin’s Weindruch, one of his protégés, he wrote a magisterial tome on calorie restriction, as well as highly enthusiastic consumer-health books on CR that make many gerontologists wince.

The biosphereans had planned to be totally self-sufficient, growing all the food they needed within the self-enclosed structure in order to emulate an extraterrestrial living experience. When their harvests fell short, they found themselves acting as guinea pigs in a CR study in which their calorie intake was chopped by 20 to 25 percent. (Gerontologist Richard Miller points out that the biosphereans’ calorie intake might not have fallen if they had been willing to eat cockroaches, which multiplied wildly inside their structure and devoured much of their food.)

Walford closely tracked how they fared on their low-calorie, nutritionally adequate rations and later coauthored a report concluding that the biosphereans’ hormonal, blood-chemistry, and other physiological changes had looked a lot like those of rodents on CR. Moreover, they kept up a high level of physical and mental activity. But a photograph of Walford after he had been inside the Biosphere for fifteen months, which was included in the study he published after it was all over, showed him looking emaciated and prematurely aged. A buildup of toxic nitrous oxide and a reduced oxygen level inside the structure might have contributed to the ill effects.

He died in 2004 at age seventy-nine of amyotrophic lateral sclerosis, the neurodegenerative disease that killed Lou Gehrig, which is apparently one of the very few illnesses made worse by CR. The night before he died, his daughter told the Los Angeles Times, he was fiercely working away on a Biosphere documentary video, his enfeebled arms suspended by pulleys over a computer keyboard.

For all the evidence suggesting that calorie restriction can significantly increase our health spans and life expectancy, there is little data in the CR literature to support the idea that it really slows human aging. That’s another paradoxical-sounding statement that’s really not paradoxical at all. As explained in chapter 2, proving that an intervention has anti-aging power requires showing, minimally, that it extends not average life span (life expectancy) but maximum life span. And that, of course, isn’t feasible with CR in people, given that it would entail a study that goes on for something like a century.

But there is one human data set that some gerontologists regard as showing that CR has extended maximum life span. Researchers have known since 1949 that the calorie content of traditional diets on Okinawa, a multi-island prefecture of Japan, has been extraordinarily low even by Japanese standards. Data collected in the 1970s showed that adult Okinawans’ calorie intake was 83 percent of Japan’s average at the time. Thus, it seems likely that older Okinawans have spent most of their lives on what’s considered a mild CR regimen.

It’s probably no coincidence that Okinawans are the longest-living group of people in the world. In 1995, the longest-living 1 percent of Okinawans survived, on average, 104.9 years, nearly 4 years more than the comparable figure in the United States, and in Japan as a whole as well.

Okinawans also appear to experience compressed morbidity. They have 80 percent less breast cancer and prostate cancer than North Americans do. They have little heart disease; one autopsy of an Okinawan centenarian showed that her coronary arteries were virtually free of fatty deposits that precipitate heart attacks. Elderly Okinawans have about 40 percent fewer hip fractures than their U.S. peers. Their prevalence of dementia between ages eighty-five and ninety is half that of Americans.

Of course, other factors, such as the emphasis on vegetables and fish in Okinawans’ traditional diets (but not in their increasingly Westernized ones), lots of manual labor, and the possibility that they carry longevity-promoting genes, may have contributed to their long lives and health spans. But these days it wouldn’t seem the least bit heretical to suggest that their low-calorie diets have been one of the most important factors.